-
[show abstract]
[hide abstract]
ABSTRACT: To investigate the effects of hyperbaric oxygenation (HBO) on regeneration of the biliary ductal system and postoperative cholestasis in hepatectomized rats.
HBO was performed in Wistar rats daily starting 12 h after a 70% partial hepatectomy. Regenerated liver weight, serum parameters and the proliferating cell nuclear antigen labeling index of hepatocytes and biliary ductal cells were measured. Hepatocyte growth factor (HGF), c-Met and transforming growth factor (TGF) β-1 mRNA expression levels were analyzed by quantitative reverse transcription polymerase chain reaction.
HBO improved the postoperative serum levels of total bile acid but not transaminase levels. HBO promoted hepatocyte and biliary ductal cell proliferation. The hematoxylin and eosin-stained specimens revealed fewer ballooned hepatocytes and higher cell densities in the HBO group compared to the control group. HBO suppressed c-Met mRNA levels at 15 h but did not modulate HGF or TGF β-1 mRNA expression levels.
HBO promoted regeneration of biliary ductal cells and improved postoperative cholestasis after a partial hepatectomy.
World Journal of Gastroenterology 05/2011; 17(17):2229-35. · 2.47 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A 29-year-old man with advanced hilar cholangiocarcinoma was successfully treated with an extended right lobectomy. The carbohydrate antigen 19-9 (CA19-9) level was elevated to 939 IU/l, and the pathological findings revealed moderately differentiated tubular adenocarcinoma which involved almost the entire thickness of the hepatic duct and the adjacent liver tissue (T3) and which was associated with lymph node metastasis (N1). It was a stage IIB (T3N1M0) tubular adenocarcinoma according to UICC pathological staging. Immunohistochemical examination revealed that Ki-67, cyclin D1, and MMP-7 were positive, and 14-3-3sigma and p27 were negative. The pathological and immunohistochemical findings indicated high malignant potential indicating poor prognosis. We administrated the postoperative adjunct gemcitabine combined with S-1 chemotherapy. The patient is alive without recurrence and doing well two years after surgery. We also review other reports of cholangiocarcinoma patients aged less than 30 years.
Case Reports in Gastroenterology 01/2010; 4(2):144-152.
-
[show abstract]
[hide abstract]
ABSTRACT: Using magnetic resonance imaging (MRI), changes in the livers of postoperative biliary atresia (BA) patients were investigated.
Periodic MRI was performed in 32 postoperative BA patients. The findings were evaluated by calculating the near-normal liver tissue area that corresponded with normal- or high-signal regions on T1-weighted imaging. The patients were divided into three groups based on the extent of near-normal liver tissue on the final MRI: group A, n = 14; group B, n = 13; and group C, n = 5, included patients with >40%, 20-40%, and <20% area of near-normal liver tissue, respectively. The relationship among the macroscopic and histological findings in the liver at orthotopic living donor liver transplantation (OLDLT), patient outcomes, and MRI findings were investigated.
In group A, 11 patients had no evidence of liver dysfunction. In group B, six patients either had undergone or were awaiting OLDLT. In group C, all patients had undergone OLDLT. All patients had either adequate or impaired bile drainage in each liver segment. The segmental changes corresponded with the liver architecture at OLDLT. The changes could be evaluated on MRI at 1-2 years after surgery.
Adequate and restricted areas of liver tissue with near-normal structure were indicative of good and poor prognoses, respectively. Shortly after portoenterostomy, these segmental changes occurred and/or developed in each liver segment and could be detected on MRI. It is emphasized that patients with >40% area of near-normal liver architecture at the initial stages did not require OLDLT, while those with <20% area did require OLDLT.
Pediatrics International 02/2009; 51(1):66-70. · 0.63 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have reported that the levels of the soluble molecule of the human leukocyte antigen class I (sHLA-I) in patients with advanced gastric cancer were significantly lower than those in patients with cancer in the early stages. However, the effect of sHLA-I on gastric cancer cells has not been elucidated. Using human gastric cancer cell lines, MKN28, MKN45, and MKN74, we evaluated the effects of sHLA-I on cell growth, DNA synthesis, and apoptosis induction. Three types of synthesized peptides derived from HLA-I were also examined for their capacity to induce apoptosis. sHLA-I and a synthesized peptide, nos. 220-232 of the alpha3 domain of HLA-B7, caused cell growth inhibition by inducing apoptosis in human gastric cancer cells. This peptide also inhibited the in vivo growth of cancer dissemination caused by an intraperitoneal injection of MKN45 into severe combined immunodeficient mice. In conclusion, sHLA-I and the peptides derived from HLA-I cause apoptosis in human gastric cancer cell lines.
Digestive Diseases and Sciences 06/2008; 54(1):63-9. · 2.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To investigate the effect of 90% partial hepatectomy (90% PHx) and the involvement of bile on ileal motility in conscious rats.
Two strain gauge force transducers were chronically implanted in the ileum of each of 20 rats. The rats were divided into four groups, three of which underwent 90% PHx. The experiments were performed with the rats in a conscious, fasted state. After ileal motility was recorded, bile or saline was perfused into the duodenum of each rat in two of the 90% PHx groups. The effects of the perfusion on ileal motility were observed and recorded using the motility index (MI), defined as the area under the contraction cues after surgery and expressed as the ratio to the MI in the preoperational motility. The time of the first passage of stool after surgery was recorded.
A typical migrating motor complex (MMC) pattern was observed in normal fasted rats. Increased MMC cycle lengths and a decreased MI at 1 day and 3 days after 90% PHx were observed. The MMC after 90% PHx was characterized by an increased duration of Phase 2-like activity. The MMC cycle length, the MI, and the time of the first passage of stool after 90% PHx were improved by perfusion of bile into the duodenum through the biliary cannula but were not influenced by perfusion of saline into the duodenum through the biliary cannula.
The MMC cycle length and the MI were inhibited after 90% PHx, with the involvement of decreased bile flow into the gastrointestinal tract by liver resection.
Journal of Surgical Research 04/2008; 150(1):131-6. · 2.25 Impact Factor
-
Atsushi Takahashi,
Makoto Hasegawa,
Ryo Sumazaki,
Makoto Suzuki,
Fumiaki Toki, Taketoshi Suehiro,
Kazumichi Onigata,
Takeshi Tomomasa,
Tomoko Suzuki,
Akira Matsui,
Akihiro Morikawa,
Hiroyuki Kuwano
[show abstract]
[hide abstract]
ABSTRACT: The authors report the case of a boy with PFIC type 2 or BRIC type 2 who suffered from liver dysfunction at 2 months after birth.
A liver biopsy specimen revealed mild liver cirrhosis, and the findings resembled those observed in Byler disease. Genetic examination revealed a normal familial intrahepatic cholestasis-1 gene, but a heterozygous mutation for the ABCB11, C1620A (F540L), was observed. Therefore, the patient was initially diagnosed with PFIC type 2. For 3 years after the diagnosis, he had severe pruritus, an increased serum bile acid, and normal serum values of gamma-glutamyl transaminase. At the age of 2, treatment with administration of ursodeoxycholic acid was started; subsequently, a gradual improvement in his liver function was observed. At the age of 3, he suffered from massive intestinal and pulmonary hemorrhage, which improved immediately after the administration of vitamin K. He was then admitted to our hospital for liver transplantation. At 1 month after the admission, his liver dysfunction showed further improvement, except for a mild increase in the serum bile acid level. This condition did not show any change during the 5-year follow-up period. In addition, the patient showed severe growth failure and was diagnosed with growth hormone deficiency. Hence, he receives growth hormone administration.
The patient could be genetically diagnosed with bile salt export pump disease of PFIC type 2 or BRIC type 2. Various clinical features are observed in PFIC or BRIC patients with ABCB11 mutation.
European Journal of Gastroenterology & Hepatology 12/2007; 19(11):942-6. · 1.76 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Pancreatic fistula is a major problem in minimal invasive surgery of the pancreas. To prevent the disruption of the pancreatic duct, the surgeon must recognize the site of the pancreatic duct exactly.
We reviewed the cases of 7 patients who underwent preoperative endoscopic pancreatic stenting for the prophylaxis of pancreatic fistula development after enucleation of a benign pancreatic head tumor.
Preoperative endoscopic pancreatic stenting was successfully performed in all 7 patients. The level of serum amylase increased to 1500 IU/L on postoperative day 1, but levels recovered to normal within 3 days. None of the patients developed a pancreatic fistula.
Preoperative pancreatic duct stenting is a feasible, effective, and safe technique to prevent pancreatic duct disruption during enucleation of a benign tumor of the pancreatic head.
American journal of surgery 11/2007; 194(4):553-5. · 2.36 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The indication of preoperative portal vein embolization (PVE) has been expanded to hepatocellular carcinoma, cholangiocellular carcinoma (CCC), hepatic metastasis, and gallbladder (GB) cancer as well as hilar cholangiocarcinoma (hCC). However, biliary cancers sometimes cause peritoneal dissemination.
We performed our preoperative trans-ileocecal-vein PVE (TIPE) method on 14 (3 GB cancer, 1 CCC, and 10 hCC), whose estimated residual liver volume was <30%.
Out of 14 patients, peritoneal dissemination was encountered in two patients with GB cancer and one with hCC (21.4%) during our procedure. The estimated residual liver volume was 37.4 +/- 2.7% at 14 days after PVE in patients without predisposing cholangitis, while those in patients with cholangitis was 29.3 +/- 1.3% (P = 0.0002). No major complication due to the procedure was encountered in this series.
PTPE could be the first choice for patients with hCC, hepatocellular carcinoma, and hepatic metastases. Although the TIPE proposed here has some potential disadvantages, we would recommend it especially for patients with GB cancer because of its high potential to cause cancerous peritonitis. When a patient had predisposing cholangitis, radical operation should be scheduled on >21 days after PVE rather than on 14 days.
Journal of Surgical Oncology 10/2007; 96(5):438-41. · 2.10 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A complete resection of a hepatocellular carcinoma (HCC) producing the granulocyte colony-stimulating factor (G-CSF) was performed and is reported here. The patient had a few general symptoms and complications, such as the paraneoplastic syndrome. He had marked granulocytosis, and his serum levels of G-CSF and interleukin-6 were elevated. The pathological findings of the resected specimen revealed poorly differentiated HCC with sarcomatous change and showed, immunohistochemically, staining of G-CSF. Only a few cases of G-CSF-producing HCC have been reported, and they resulted in rapid tumour growth and poor prognosis. The case presented here may be the first complete resection ever performed, but the patient's prognosis was similar to that observed in typical cases.
Liver international: official journal of the International Association for the Study of the Liver 07/2007; 27(5):716-21. · 3.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A soluble form of human leukocyte antigen class I antigen (sHLA-I) has been reported to cause apoptosis on cytotoxic T cells and inhibit killer activity of natural killer cells via killer-cell inhibitory receptors. However, its effect on cancer cells has not yet been elucidated. We examined the direct effect of sHLA-I on human liver cancer cell lines, HepG2, HLE and HLF. The effects of sHLA-I on cell growth, DNA synthesis, and apoptosis induction were evaluated. To elucidate the mechanisms, cDNA expression arrays were also examined. sHLA-I caused cell growth inhibition, resulting in apoptosis on human hepatocellular carcinoma, dose-dependently. In this process, caspase-3 was activated. sHLA-I also inhibited in vivo growth of hepatocellular carcinoma in severe combined immunodeficient mice. sHLA-I caused apoptosis on human hepatocellular carcinoma.
Oncology Reports 01/2007; 16(6):1375-80. · 1.84 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Laparoscopic ligation of the peripancreatic vessels or duct requires a particularly skillful technique. If the pancreatic tail and the spleen can be mobilized outside of the abdominal cavity, surgeons can perform these procedures as easily as ordinary open surgery. We developed a novel approach to laparoscopy-assisted distal pancreatectomy without hand-assist. In brief, the pancreatic tail and the spleen were mobilized laparoscopically from the retroperitoneum until the celiac axis was exposed, then the pancreatic tail and the spleen were laparoscopically mobilized outside the peritoneal cavity from a small incision at the upper abdomen. After mobilization, the distal pancreatectomy was performed as usual open method. This approach offers better results in coping with organs, which seem to be difficult to resect through laparoscopic surgery alone.
Surgical laparoscopy, endoscopy & percutaneous techniques 01/2007; 16(6):387-9. · 1.23 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Right-lobe grafts without the middle hepatic vein (MHV) can cause severe congestion of the anterior segment in living-donor liver transplantation (LDLT). However, the indications and methods for reconstructing the MHV or its tributaries remain controversial.
We herein describe two cases of the successful use of the recipient's recanalized umbilical vein as an interposition graft to drain the major MHV tributaries in right-lobe LDLTs.
After surgery, both right-lobe grafts are currently functioning well and all of the reconstructed venous tributaries have been confirmed to be patent by doppler ultrasonography. The histopathological features of the recanalized umbilical vein showed an intact intima with thickened media.
The use of the recipient's recanalized umbilical vein is a good option for reconstructing MHV tributaries in right-lobe LDLTs.
Surgery 04/2006; 139(3):442-5. · 3.10 Impact Factor
-
Yoshimi Nakajima,
Hitoshi Takagi,
Naondo Sohara,
Ken Sato,
Satoru Kakizaki,
Kenichi Nomoto,
Hideki Suzuki, Taketoshi Suehiro,
Tatsuo Shimura,
Takayuki Asao,
Hiroyuki Kuwano,
Masatomo Mori,
Ken Nishikura
[show abstract]
[hide abstract]
ABSTRACT: A 42-year-old woman was admitted to our hospital because of multiple liver tumors detected by ultrasonography. Colonoscopy revealed submucosal tumor in the rectum, which was considered the primary lesion. Endoscopic mucosal resection followed by histopathological examination revealed that the tumor was carcinoid. The resected margin of the tumor was positive for malignant cells. Two courses to transcatheter arterial chemotherapy for liver metastasis were ineffective. Accordingly, the rectal tumor and metastatic lymph nodes were surgically resected. One month after the operation, she received liver transplantation (left lateral segment and caudate lobe) from her son. No recurrent lesion has been observed at two years after the liver transplantation. Liver transplantation should be considered as a treatment option even in advanced case of carcinoid metastasis to the liver. We also discuss the literature on liver transplantation for metastatic carcinoid tumor.
World Journal of Gastroenterology 04/2006; 12(11):1805-9. · 2.47 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hepatic grafts from hepatitis B surface antigen-negative and anti-core antibody (HBcAb)-positive donors have been shown to transmit hepatitis B virus (HBV) infection. Recently, it has been reported that combined hepatitis B immune globulin (HBIG) and lamivudine therapy is effective in the prevention of hepatitis B recurrence after living donor liver transplantation (LDLT). In this report, we assessed the efficacy of combined HBIG and lamivudine therapy in preventing HBV transmission by graft with HBcAb-positive donors.
We studied 22 patients who had undergone LDLT with allografts from HBcAb-positive living donors at Gunma University Hospital and Kyushu University Hospital. Long-term combined HBIG and lamivudine therapy were administrated to all recipients. Serum samples from the donor and recipient were tested for HBcAb, HBV DNA, and hepatitis B surface antibody. Liver biopsies from grafts were tested for HBV DNA.
All recipients were HBcAb negative before LDLT. All of the donor livers were HBV DNA positive at the time of LDLT. All of the recipients had HBsAb titers greater than 300 mIU/ml 4 weeks after LDLT, and remained 100 mIU/ml thereafter. None of the recipients have become infected with HBV with a follow-up of 25-86 months.
Perioperative combined HBIG and lamivudine therapy can prevent HBV infection in recipients who receive liver grafts from HBcAb-positive donors.
Liver international: official journal of the International Association for the Study of the Liver 01/2006; 25(6):1169-74. · 3.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Reports on the relevance of immunogenetic factors in living donor adult liver transplantation (LDALT) are often conflicting or inconclusive. We therefore investigated the human leukocyte antigen (HLA) mismatches, lymphocyte crossmatch positivity, and the reactivity in mixed lymphocyte culture (MLC) in a series of LDALT.
A total of 104 LDALT patients were studied. The minimum follow-up was 12 months, and the graft survival rates were assessed. The incidence of the most common complications was analyzed. And the influence of HLA, the flow cytometric analysis findings, enhanced cytotoxic cross-matching and MLC on graft survival, and acute rejection was also investigated.
As a result, 96 negative cross-matching and eight positive cross-matching cases were identified. Positive cytotoxic cross-matching had a significant effect on graft survival (P<0.05), while flow cytometric cross-matching also had an additional effect on acute rejection (P<0.05). The MLC of the patients with three HLA mismatches was significantly higher than the MLC of patients with zero HLA mismatches. The incidence of acute cellular rejection (ACR) was higher in the patients with three mismatches than in the other patients, and moderate rejection only occurred in the patients with three mismatches.
HLA mismatching was not statistically associated with the overall graft survival after LDALT. The graft failure rates were higher in the positive cross-matching cases and therefore a strong immuosuppressant might be needed for positive cross-matching cases.
Liver international: official journal of the International Association for the Study of the Liver 12/2005; 25(6):1182-8. · 3.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Bile leakage after living donor liver transplantation (LDLT) remains a serious problem, resulting in lower survival rates. The aim of this study is to clarify the benefits of in situ leakage testing of the cut surface of grafts in LDLT.
A total of 135 LDLTs were analyzed. The patients were divided into the following two groups according to the in situ dye injection leakage test of the cut surface: test group (n=40) and control group (n=40). The incidence of bile leakage and the risk factors were identified by analyzing the recipients, donors, and transplantation variables.
Bile leakage occurred in 12.5% (10/80) of LDLTs. In the control group, there were nine cases of bile leakage (22.5%). On the other hand, there was only one case (2.5%) of bile leakage in the test group (P<0.05). The bile leakage case in the test group was resolved preservationally. However, 2 of the 9 (22.2%) bile leakage cases in the control group required surgery.
Although there is biliary complication, especially bile leakage from the cut surface, as an inevitable consequence of LDLT, this study suggests that there is advantage in conducting bile leakage testing to minimize the incidence of bile leakage from the cut surface, which is associated with a high risk of graft failure.
Transplantation 12/2005; 80(10):1398-401. · 4.00 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hepatic venous reconstruction is critical in living donor adult liver transplantation (LDALT) because outflow obstruction in small for size graft may lead to graft dysfunction or loss. We describe the usefulness of venoplasties of the graft hepatic vein (HV) and graft HV-recipient inferior vena cava (IVC) reconstruction in LDALT using a left lobe graft.
Sixty patients who underwent LDALT were studied. We divided the patients into following two groups: venoplasty group (n=30) and control group (n=30). For the patients with venoplasty group, venoplasty of the graft and recipient IVC cavoplasty was made to widen the orifice. Comparison examination of a background factors and postoperative bilirubin and the ascites was carried out.
The mean graft volume standard liver volume ratio (GV/SLV) did not have the difference at 41.7% of venoplasty group, and 42.1% of control group (p=NS). The diameter of the hepatic vein in control and venoplasty group before and after venoplasty is 26.9+/-5.5, 28.2+/-2.9, and 34.1+/-3.9 mm, respectively. The diameter of the hepatic vein after venoplasty is larger than that of before venoplasty and of control (P<0.05). Mean total bilirubin level on postoperative day (POD) 7 is 13.8+/-9.3 mg/dl in control group and 7.0+/-3.3 mg/dl in venoplasty group (P<0.05). Mean amount of ascites on POD 7 and 14 are 1576+/-1113 and 1397+/-1661 cc in control group, and 736+/-416 and 550+/-385 cc in venoplasty group, respectively (P<0.05). Two-year survival rate is 75.2 % in control group and 86.6 % in venoplasty group (P<0.05).
We conclude that in LDALT using left lobe graft, HV-IVC reconstruction with graft venoplasty and IVC cavoplasty is useful not only to prevent outflow block but also to improve graft function.
Transplantation 11/2005; 80(7):964-8. · 4.00 Impact Factor
-
Taketoshi Suehiro,
Mitsuo Shimada,
Keiji Kishikawa,
Tatsuo Shimura,
Yuji Soejima,
Tomoharu Yoshizumi,
Kohji Hashimoto,
Yasushi Mochida,
Shinji Hashimoto,
Yoshihiko Maehara,
Hiroyuki Kuwano
[show abstract]
[hide abstract]
ABSTRACT: The most important problem in the living donor adult liver transplantation (LDALT) is a small for size graft. Although a right lobe graft is used in many cases in order to avoid small for size graft, for a donor, the risk has few in left lobe graft. We evaluate the effect of an intraportal infusion treatment to the small for size graft. One hundred and twelve patients who underwent LDALT were studied. The graft weight recipient standard liver volume ratio (GV/SLV) of these patients were 50% or less. We divided the patients into following two groups; infusion group (n = 53) and control group (n = 59). For the infusion group, 16 G double lumen catheter was inserted into portal vein and nafamostat mesilate (protease inhibitor which stabilize coagulofibrinolytic state; 200 mg/day), prostaglandin E(1) (vasodilator and hepatoprotective effect; 500 microg/day) and thromboxane A(2) synthetase inhibitor (vasodilator and anticoagulant effect; 160 mg/day) were administrated continuously for 7 days. Small-for-size graft syndrome was defined as bilirubin >10 mg/dl and ascites >1000 cc on postoperative day (POD) 14. Comparison examination of a background factors and postoperative bilirubin and amount of ascites was carried out. The mean GV/SLV did not have the difference at 39.1% of infusion group, and 38.3% of control group (P = 0.58). By the control group, 15 patients (25.4%) were small-for-size graft syndrome, however, there was only two (3.8%) small-for-size graft syndrome in infusion group (P = 0.04). The bilirubin levels of infusion and control group on 7 and 14 POD were 9.9 and 7.8 vs. 9.5 and 10.5 mg/dl, respectively. The amount of ascites of infusion group on 7 and 14 POD were 870 and 430 cc, respectively. On the contrary, in control group, the amount of ascites on 7 and 14 POD were 1290 and 1070 cc, respectively. Bilirubin levels and the amount of ascites on 7 and 14 POD were lower in the patients with infusion group then those with control group. There were no differences between infusion group and control group in age, sex and Child's classification. The intraportal infusion had an effect in prevention of hyperbilirubinemia and loss in quality of excessive ascites in the patients with small for size graft. This was suggested to be what is depended on the improvement of the microcirculation insufficiency considered one of the causes of small-for-size graft syndrome.
Transplant International 09/2005; 18(8):923-8. · 2.92 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Although the ability of the liver to regenerate to a predetermined size after resection made adult-to-adult living donor liver transplantation (LDLT) possible, there is little information regarding the growth regulatory mechanism for a small-for-size graft. Forty-one cases of LDLT were divided into two groups by graft volume to standard liver volume ratio (GV/SLV); small graft group (Group S, GV/SLV>40%, n=16) and nonsmall graft group (Group NS, GV/SLV>40%, n=25). The regeneration rate (GV at 1 week/harvested GV) and serum levels of hepatocyte growth factor (HGF), transforming growth factor-α (TGF-α) and transforming growth factor-β1 (TGF-β1) were compared between two grous. The regeneration rates in Group S were significantly higher than that of Group NS (217, 12% and 178, 10%, respectively, P>0.01). The serum HGF levels of Group S were significalty higher than hjose of Group NS on POD 1. The TGF-β1 levels of Group S were significatly higher than those of Group NS on POD 3 and 5. The TGF-α levels were not different at any time points studied. These results indicate that a small-for-size graft retains the capacity to regenerate faster by modulation of expression pattern of HGF and TGF-β1 immediately after LDLT. After the acceleration of the regenerative response by HGF, subsequent elevation of TGF-β1 synergisically controls graft size, regulating uncontrolled proliferation of hepatocytes.
Transplant International 03/2005; 16(11):814 - 819. · 2.92 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Immunosuppressive therapy for organ transplantation is essential for controlling rejection. When liver transplantation is performed as a therapy for hepatocellular carcinoma (HCC), recurrent HCC is one of the most fatal complications. In this study, we show that intratumoral murine IL-12 (mIL-12) gene therapy has the potential to be an effective treatment for malignancies under immunosuppression. C3H mice (H-2(k)), injected with FK506 (3 mg/kg) i.p., were s.c. implanted with 2.5 x 10(6) MH134 cells (H-2(k)) and we treated the established HCC with electroporation-mediated gene therapy using mIL-12 plasmid DNA. Intratumoral gene transfer of mIL-12 elevated intratumoral mIL-12, IFN-gamma, and IFN-gamma-inducible protein-10, significantly reduced the number of microvessels and inhibited the growth of HCC, compared with HCC-transferred control pCAGGS plasmid. The inhibition of tumor growth in immunosuppressed mice was comparable with that of mIL-12 gene therapy in immunocompetent mice. Intratumoral mIL-12 gene therapy enhanced lymphocytic infiltration into the tumor and elicited the MH134-specific CTL response even under FK506. The dose of FK506 was sufficient to prevent the rejection of distant allogenic skin grafts (BALB/c mice, H-2(d)) and tumors, B7-p815 (H-2(d)) used as transplants, during mIL-12 gene therapy against MH134. Ab-mediated depletion studies suggested that the inhibition of tumor growth, neovascularization, and spontaneous lung metastasis by mIL-12 was dependent almost entirely on NK cells and partially on T cells. These results suggest that intratumoral mIL-12 gene therapy is a potent effective strategy not only to treat recurrences of HCC in liver transplantation, but also to treat solid malignant tumors in immunosuppressed patients with transplanted organ.
The Journal of Immunology 01/2005; 173(11):6635-44. · 5.79 Impact Factor
